Preleukemic states, such as aplastic anemia, sideroblastic anemia, erythremic myelosis and the "preleukemic syndrome" often demonstrate morphologic and kinetic features of folate deficiency, and occasional patients with these diseases improve with empiric trials of folic acid. Recently we began investigating one such patient, a young man with severe aplastic anemia, who has a strong family history of leukemia, neutropenia and refractory anemia. Preliminary studies suggest this patient and other family members manifest a previously undescribed defect of cellular folate uptake. Therapy with high dose folate resulted in marked clinical improvement of the aplasia. We suggest that similar defects of folate metabolism may cause hematologic abnormalities in other patients with preleukemic states and possibly contribute to leukemogenesis by altering nucleic acid metabolism. We propose to delineate more clearly the processes involved in the uptake and utilization of folate by normal human lymphocytes, bone marrow cells and red cells, and develop criteria and techniques for the identification of disorders of these processes. Using these techniques, patients with preleukemic states will be screened for evidence of impaired folate metabolism, and identified patients will be studied in detail to characterize their cellular abnormality. These patients will then be treated with high doses of folic acid and clinical response measured. An attempt will be made to assess whether this treatment alters the risk of subsequent leukemic transformation in these patients with preleukemic states.